Gram negative bacterial cell walls are more complex than Gram positive bacterial cell walls, both structurally and chemically. Structurally, a Gram negative cell wall contains two layers external to the cytoplasmic membrane, the outer membrane is like a stiff canvas sack around the bacteria. The outer membrane maintains the bacterial structure and is a permeability barrier to large molecules and hydrophobic molecules. It also provides protection from adverse environmental conditions such as the digestive system of a host (important for Enterobacteriaceae organisms). Compared with Gram-positive bacteria, Gram-negative bacteria are more resistant against antibodies and detergents. In general, Gram positive bacteria tend to persist in dry environments better and are often found on places like the skin and in dust. Gram negative bacteria, on the other hand, are killed more quickly by drying but thrive in aqueous environments. Gram negative bacteria also tend to grow better in the presence of toxic chemicals (such as chlorine), a feat thought to be enabled by their two cell membranes and which is especially problematic in the health care environment.
Gram-negative bacteria cause a variety of pathological conditions including pneumonia, bloodstream infections, wound or surgical site infections, sexually transmitted diseases including gonorrhea, and meningitis. Gram-negative bacteria are resistant to multiple drugs and are increasingly resistant to most available antibiotics. Certain types of Gram-negative bacteria have become increasingly resistant to available antibiotic drugs. Some strains are now resistant to many, most, or all available treatments resulting in increased illness and death from bacterial infections, and contributing to escalating healthcare costs. Examples of Gram-negative bacteria that have demonstrated drug resistance include:                E. coli, which causes the majority of urinary tract infections and healthcare associated blood stream infections.        Acinetobacter baumanii, which causes disease mainly in healthcare settings.        Pseudomonas aeruginosa, which causes bloodstream infections and pneumonia in hospitalized patients.        Klebsiella pneumoniae, which causes many types of healthcare-associated infections, including pneumonia, urinary tract infections, and bloodstream infections        Neisseria gonorrhoeae, which causes the sexually transmitted infection gonorrhea.        
Gram-negative bacteria can cause many types of infections and are spread to humans in a variety of ways. Several species, including Escherichia coli, are common causes of food-borne disease. Virulent strains of E. coli can cause gastroenteritis, urinary tract infections, and neonatal meningitis. In rarer cases, virulent strains are also responsible for hemolytic-uremic syndrome, peritonitis, mastitis, septicemia and Gram-negative pneumonia.
K. pneumoniae can cause pneumonia and can cause destructive changes to human lungs, inflammation and hemorrhage with necrosis. Typically these bacteria gain access after a person aspirates colonizing oropharyngeal microbes into the lower respiratory tract. The most common infection caused by Klebsiella bacteria outside the hospital is pneumonia, typically in the form of bronchopneumonia and also bronchitis. These patients have an increased tendency to develop lung abscess, cavitation, empyema, and ural adhesions. The disease has an alarmingly high death rate of about 50% even with antimicrobial therapy and the mortality rate can be nearly 100% for persons other compromising conditions such as with alcoholism and bacteremia. Within the healthcare setting, nosocomial pneumonia is the second-most-common nosocomial infection, the disease adds significantly to the cost of hospital care and to the length of hospital stays.
In addition to pneumonia, Klebsiella can also cause infections in the urinary tract, lower biliary tract, and surgical wound sites. The range of clinical diseases includes pneumonia, thrombophlebitis, urinary tract infection (UTI), cholecystitis, diarrhea, upper respiratory tract infection, wound infection, osteomyelitis, meningitis, and bacteremia. If a person has an invasive device in their body then contamination of the device becomes a risk; for example respiratory support equipment and urinary catheters put patients at increased risk. Also, the use of antibiotics can be a factor that increases the risk of nosocomial infection with Klebsiella bacteria.
Of the Gram-positive bacteria, S. epidermidis is usually non-pathogenic, however these bacteria are responsible for a growing number of infections among hospital patients whose immune systems are weakened or compromised and in immuno-competent individuals with indwelling medical devices. Such infections often occur because the bacterium is carried from the surface of the skin to deeper tissues and the blood stream by insertion of venous catheters or peritoneal dialysis catheters. These infections can be both nosocomial or community acquired, but they are more of a threat to hospital patients. This is in part due to hospitals harboring more virulent strains of the organism and the continuous use of antibiotics and disinfectants. S. epidermidis is a major concern for individuals with catheters or other surgical implants because it is known to cause biofilms that grow on such devices, especially on intravenous catheters and on medical prostheses. Infection can also occur in dialysis patients or anyone with an implanted medical device that may have been contaminated. S. epidermidis has also been associated with endocarditis and occurs most frequently in patients with defective heart valves. It is also responsible for the majority of late-onset sepsis in newborns.
To survive during colonization or infection of the human body, microorganisms must circumvent mechanisms of innate host defense. Antimicrobial peptides (also known as natural antibiotics) represent a key component of innate host defense, especially in phagocytes and on epithelial surfaces. Antimicrobial peptides derived from humans and other higher animals are potent, broad-spectrum antibiotics and those of bacterial origin tend to have a more focused spectrum of activity. Both types of peptide demonstrate potential as alternative novel therapeutic agents. The interaction of the peptides with susceptible cells is thought to occur via ionic interactions and results in cell death by destabilization of the membranes and/or pore formation. Epidermicin is a bactericidal peptide with rapid and potent activity against a wide range of gram-positive pathogens.
WO2011/073663 describes the identification, purification, characterization and expression of epidermicin, an antimicrobial peptide which is an unmodified or native bacteriocin produced by Staphylococcus epidermidis strain 224. The natural peptide of WO2011/073663 is a highly cationic, hydrophobic, plasmid-encoded peptide that exhibits potent antimicrobial activity toward a wide range of pathogenic Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), enterococci, and biofilm-forming S. epidermidis strains.
However, the increasing resistance of bacteria to many synthetic antibiotics emphasizes the urgent need for new and more effective antimicrobial agents. There is a need for new and effective preventive and therapeutic treatments for bacterial infections, especially against Gram-negative bacterial infections and ideally in conjunction with the ability to also concomitantly treat Gram-positive infections.